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Arq. Bras. Cardiol. vol.101 no.3 São Paulo Sept. 2013 Epub July 23, 2013
Roberta Aguiar SarmentoI,II; Flávia Moraes SilvaII; Graciele SbruzziI; Beatriz D'Agord SchaanI,II,III; Jussara Carnevale de AlmeidaII,III
IInstituto de Cardiologia do Rio Grande do Sul - Fundação Universitária de Cardiologia, Porto Alegre, RS
IIServiço de Endocrinologia do Hospital de Clínicas de Porto Alegre - Universidade Federal do Rio Grande do Sul, Porto Alegre, RS
IIIDepartamento de Medicina Interna - Faculdade de Medicina da Universidade Federal do Rio Grande do Sul, Porto Alegre, RS - Brazil
BACKGROUND: Inverse associations between micronutrient intake and cardiovascular outcomes have been previously shown, but did not focus on diabetic patients.
OBJECTIVE: To systematically review the role of micronutrients in the development/presence of cardiovascular outcomes in patients with diabetes.
METHODS: We searched Medline, Embase, and Scopus (January/1949-March/2012) for observational studies that evaluated micronutrients and cardiovascular outcomes in patients with diabetes, and then selected and extracted the data (two independent reviewers).
RESULTS: From the 15 658 studies identified, five were included, comprising three case-control and two cohorts, with a follow-up of 7-15 years. A meta-analysis was not performed due to the different antioxidant micronutrients (types and measurement methods) and outcomes evaluated. The micronutrients assessed were vitamin C intake in diet and/or supplementation, chromium and selenium in toenail samples, and α-tocopherol and zinc in serum levels. Intake of >300 mg of vitamin C through supplementation was associated with increased risk of cardiovascular disease, coronary artery disease (CAD), and stroke (RR 1.69-2.37). High levels of α-tocopherol in serum were associated with 30% lower CAD risk in another study (HR 0.71; 95%CI 0.53-0.94). Among minerals (zinc, selenium, and chromium), an inverse association between zinc and CAD was observed; levels lower than 14.1 µmol/L were associated with an increased risk for CAD (RR 1.70; 95%CI 1.21-2.38).
CONCLUSION: The information available on this issue is scarce. Further prospective studies are needed to elucidate the role of these nutrients in the cardiovascular risk of patients with diabetes.
Keywords: Micronutrients; Antioxidants; Risk Factors; Cardiovascular Diseases; Diabetes Mellitus.
Biological research supports a key role for oxidative stress in atherogenesis; free radical-mediated damage induces oxidative changes in low-density cholesterol particles that initiate and promote atherosclerotic changes. This process could be reversed or prevented by the use of antioxidants1. Observational studies have shown inverse associations between antioxidant intake and cardiovascular events2, but randomized clinical trials have not shown any benefit of antioxidants in cardiovascular events3. However, these studies did not focus on patients with diabetes mellitus (DM), a population with high cardiovascular disease risk.
Coronary and cerebrovascular diseases, which are caused primarily by atherosclerosis, are the major cause of morbidity and mortality in patients with DM4, and occur more frequently and more severely in these patients5. Hyperglycemia in DM is characterized by a high oxidative stress state6, which is closely related to the genesis of chronic complications of diabetes, including cardiovascular diseases7. Particular attention has been given to the applicability of antioxidant therapy (endogenous enzymes and dietary substances) in the prevention and management of diabetic complications, especially atherosclerotic cardiovascular disease8.
Lifestyle changes and a healthy diet are included in the prevention and/or treatment of atherosclerosis in patients with or without DM. High intake of fruits, vegetables, whole grains, and oil seeds and low intake of sodium are usually recommended9. Epidemiological studies have shown that certain foods with antioxidant properties are associated with a reduction in inflammatory markers and low-density cholesterol oxidation8, and consequently, improved endothelial function10.
The aim of this study was to systematically review the role of vitamins (vitamins A, C, and E) and minerals (zinc, selenium, chromium, manganese, and copper) with antioxidants properties in the presence or development of clinical cardiovascular outcomes in patients with DM.
The search was performed to select observational studies that evaluated the role of antioxidant micronutrient intake (vitamins and minerals) in the presence or development of cardiovascular events in patients with DM. The databases used in the search were Medline from Pubmed, Embase, and Scopus for the period from January 1949 to March 2012. The search strategy included terms referring to antioxidant micronutrients: "micronutrients," "antioxidant micronutrient," "trace elements," "biometals," "antioxidants," "vitamins," "antioxidant vitamins," "vitamin C," 'ascorbic acid," 'vitamin E," "tocopherols," "alfa-tocopherol," "β-carotene," "vitamin A," "pro-vitamin A," "minerals," "antioxidant minerals," "diet," "diet therapy," "zinc," "copper," "manganese," "chromium," "selenium", to patients (type 1 or type 2 DM): "Diabetes Mellitus, Type 1," "Diabetes Mellitus, Insulin-Dependent," "Diabetes Mellitus, Juvenile-Onset," "Diabetes Mellitus, Sudden-Onset," "Diabetes Mellitus, Type I," "IDDM," "Diabetes Mellitus, Brittle," "Diabetes Mellitus, Ketosis-Prone," Autoimmune Diabetes, "Diabetes Mellitus, Type 2," "Diabetes Mellitus, Ketosis-Resistant," "Diabetes Mellitus, Non-Insulin-Dependent," "Diabetes Mellitus, Slow-Onset," Stable Diabetes Mellitus, "Diabetes Mellitus, Type II," NIDDM, "Diabetes Mellitus, Adult-Onset," "Diabetes Mellitus, Noninsulin Dependent," "Maturity-Onset Diabetes Mellitus," and type of study (observational), using a previously validated list of terms available at: http://www.sign.ac.uk/methodology/filters.html#obs.
The search strategy described above was used to identify studies on Pubmed. Similar terms were searched for in other databases. There was no restriction of the language used in the publications. The article references included in this review were consulted to identify other potentially eligible studies.
Inclusion and exclusion criteria
We included observational studies (case-control studies and cohorts irrespective of their prospective or retrospective nature) that evaluated the role of antioxidant micronutrient intake (from diet and/or supplements) in the presence or development of major cardiovascular events such as myocardial infarction or revascularization, stroke, sudden death, and death from cardiovascular causes in patients with type 1 or type 2 DM.
In selecting the studies, the antioxidant micronutrients looked at were vitamin A (beta-carotene), vitamin C (ascorbic acid), vitamin E (tocopherol), zinc, selenium, chromium, manganese, and copper. The outcomes considered were major cardiovascular events (cardiovascular death, stroke, myocardial infarction, and myocardial revascularization) and their individual components (fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, sudden death or myocardial revascularization).
Study selection and data extraction
Two reviewers (R.A.S. and F.M.S.) independently reviewed the titles and abstracts of each article identified in the literature search. In this first stage all articles that clearly did not meet the inclusion criteria were rejected. The selected articles were analyzed by reading the full text, and the eligible articles were then identified. Disagreements between reviewers at this stage of article analysis were resolved by discussion. The concordance, estimated by Kappa coefficient, was good (Kappa = 0.79).
Data extraction from each study included in this review was conducted independently by two reviewers (R.A.S. and F.M.S.) using a standardized instrument. The data extracted were publication identification, study design, sample size, follow-up duration (in cohort studies), and participants' general characteristics (type of DM, age, gender, body mass index, diabetes treatment, hypertension, and smoking). The data on diet characteristics and micronutrient antioxidants evaluated (quantity, measurement unit, and assessment method) were also extracted. The data extracted concerning cardiovascular outcomes were event type, case numbers, and the estimated risk as presented in the manuscript [relative risk (RR), odds ratio (OR), or hazard ratio (HR)]. We extracted the risk estimate data that considered the largest number of covariates in the analyses.
Quality assessment of studies
The methodological quality of each study included in this review was assessed independently by two reviewers (R.A.S. and F.M.S.) from a questionnaire developed by the authors. The questionnaire was based on four instruments for quality assessment of observational studies designed by the Scottish Intercollegiate Guidelines Network and Critical Appraisal Skills Programme, as proposed in the Cochrane Handbook11. The questionnaire included issues related to the study aim (clarity and specificity), the inclusion and exclusion criteria used to select the participants, sample size of groups, number of patients lost from each group, assessment form of exposure status to the factor studied, and outcomes (if standardized assessment was made by blinded investigators as to the participant exposure status).
From the 15 658 articles identified, 2865 were excluded because they were duplicated among the databases searched. After analysis of titles and abstracts, 12 766 articles were excluded because they did not meet the inclusion criteria and 27 articles were selected for reading the full text. After evaluating the full texts, 22 articles were excluded because of the following criteria: five studies were not observational, one study involved patients with pre-diabetes and without diabetes, three studies did not assess antioxidant micronutrient effect, seven studies did not evaluate cardiovascular outcomes, and six studies included DM as a covariate in estimating cardiovascular risk and sub-analyses did not include only patients with DM. New articles were not identified from the reference lists of studies consulted. Therefore, five studies were included in this review12-16. The study selection flow diagram is shown in Figure 1.
General characteristics of the studies
The main characteristics of the five studies included are described in Table 1. Three of them presented a case-control design12,14,15 and two were cohort studies13,16 with a follow-up ranging from 716 to 15 years13. One study was conducted in patients with type 1 DM15, one study included patients with type 2 DM16, and in one manuscript the authors reported that the majority of the participants had type 2 DM13. The other two studies did not specify the type of diabetes12,14. Sample size ranged from 12115 to 1923 participants13. The age of the patients ranged from 34 to 75 years. Two studies included both men and women15,16, two studies were performed only in men12,14, and one study was conducted only in women13. Two studies described the treatment of DM; in one of them most of the participants were using oral antidiabetic agents16; whereas in the other study, approximately 70% of patients were using insulin and/or oral antidiabetic agents13. Only two studies reported the number of hypertensive participants, current smokers, and the waist-to-hip ratio values13,15.
Different antioxidant micronutrients were evaluated in the studies and different methods were used to measure them. Vitamin C provided in dietary intake and/or supplementation was assessed by food frequency questionnaire13, chromium and selenium were quantified in samples12,14, and α-tocopherol and zinc were measured in serum15,16. The usual diet composition was not described in any study, only a partial dietary description of saturated fatty acids, vitamin E, and beta-carotene was reported in one study13.
Cardiovascular outcomes were differently evaluated among the studies: two studies evaluated the presence of cardiovascular disease12,14, two reported the presence of coronary artery disease15,16 and one other study reported mortality by cardiovascular disease, coronary heart disease, and stroke13. Because of these differences we could not perform a meta-analysis of the data extracted. Therefore, the main results of each study included in this review are shown in Table 2 and discussed.
Main findings of the studies
Antioxidant vitamins and cardiovascular outcomes
The role of antioxidant vitamins in cardiovascular disease development was evaluated in two studies13,15.
The relationship between vitamin C intake (assessed by a food frequency questionnaire validated in a subsample of the study population) and cardiovascular outcomes in postmenopausal women with DM was evaluated in a prospective cohort study followed for 15 years13. Cardiovascular outcomes (cardiovascular disease mortality, coronary heart disease and stroke) were defined based on the International Classification of Diseases: the codes potentially related to the diagnoses of interest were selected according to the description in the records of local deaths (Iowa, USA). Vitamin C intake of more than 667 mg/day (diet and/or by supplementation) approximately doubled the risk of mortality from cardiovascular disease and coronary artery disease in patients with diabetes. When dietary and supplemental vitamin C were analyzed separately, only supplemental vitamin C showed a positive association with mortality endpoints: the use of at least 300 mg/day of vitamin C supplements was associated with higher risk of cardiovascular disease mortality (RR 1.69; 95%CI 1.09-2.44), coronary artery disease (RR 2.07; 95%CI 1.27-3.38) and stroke (RR 2.3; 95%CI 1.01-5.57) than using smaller quantities of supplementation.
The effect of α-tocopherol, γ-tocopherol, and retinol on the incidence of coronary artery disease in patients with type 1 DM was evaluated in a study of 54 cases and 67 controls derived from a cohort study conducted in Pittsburgh, USA15. Cases were defined by the participants who first developed coronary artery disease, as determined by one of the following criteria: physician-diagnosed angina, myocardial infarction confirmed by Q-waves on electrocardiogram, hospital records (Minnesota code 1.1 or 1.2), angiographic stenosis >50%, coronary artery bypass surgery, angioplasty, or ischemic electrocardiographic changes during the follow-up period. Serum levels of α-tocopherol >10.45 µg/ml were inversely associated with coronary artery disease (HR 0.71; 95%CI 0.53-0.94). However, when multivitamin supplement users were compared to nonusers, the protective effect of this micronutrient was observed only among supplement users (HR 0.22; 95%CI 0.10-0.49). It is noteworthy that the authors did not specifically report the type of supplement used by the study participants.
Antioxidant minerals and cardiovascular risk
The possible association between zinc, chromium and selenium and presence or development of cardiovascular events in patients with DM were evaluated by three studies12,14,16.
A cohort study with 7 years of follow-up investigated serum zinc levels as a predictor of coronary artery disease in 1050 patients with type 2 DM from Finland16. The outcomes evaluated were mortality from coronary artery disease based on medical records and death certificates, and myocardial infarction incidence according to the World Health Organization criteria (chest pain, enzyme changes and electrocardiogram). Patients with < 14.1 µmol/L of serum zinc at baseline were at higher risk of death from coronary artery disease (RR 1.7; 95%CI 1.21-2.38) and fatal and non-fatal myocardial infarction (RR 1.37; 95%CI 1.03-1.82) than patients with serum levels >14.1 µmol/L.
In a case-control study (derived from the Health Professionals Follow-up Study), toenail levels of chromium12 or selenium14 were determined in 198 male patients with DM and prior cardiovascular disease, as well as 688 male patients with DM and without cardiovascular disease. Cardiovascular disease was considered present when subjects presented fatal or non-fatal myocardial infarction as defined by the World Health Organization criteria, coronary artery bypass grafting, angioplasty or stroke. In a multivariate analysis adjusted for the other potential confounding factors, there was no association between chromium12 or selenium14 levels and cardiovascular outcomes.
Quality evaluation is shown in Table 3. None of the studies included meets all the criteria previously established to evaluate methodological quality. However, all five studies were for the purpose of answering a clear and focused question and four of them assessed the exposure status and outcomes in a standardized and valid method. The information regarding the outcomes was collected from population-based registries in the two cohort studies selected13,16. In the three case-control studies12,14,15, outcomes were measured in a valid and standardized way. Potential confounding factors were considered in analysis of data from four studies12-14,16. Only one study showed no clear results, because the authors did not describe which covariates were used for multivariate regression adjustment15. Among the three case-control studies, none of them described whether the follow-up losses were similar between the groups12,14,15. In the two cohort studies13,16, follow up duration was considered appropriate and the selection of participants was controlled for potential confounding factors.
The purpose of this systematic review was to evaluate the role of antioxidant micronutrients in the presence or development of cardiovascular events in patients with DM. However, the high clinical heterogeneity among the studies obtained hindered the performance of a meta-analysis. Moreover, information on this issue is scarce and of low quality. Vitamin C, vitamin E (α-tocopherol), zinc, selenium, and chromium were micronutrients with antioxidant properties evaluated by the case-control and cohort studies included in this review. The outcomes analyzed were myocardial infarction, stroke, myocardial revascularization, sudden death, and death from cardiovascular causes.
The use of more than 300 mg/day of vitamin C by supplementation was associated with increased cardiovascular risk13. Interestingly, this is not what is reported for subjects without diabetes2,17. A systematic review of 15 cohort studies with 374,488 subjects without DM showed an inverse association between higher intake of vitamin C (diet and supplement) and risk of coronary artery disease (RR 0.84; 95%CI 0.73-0.95)2, but the results were not confirmed with the use of supplemental vitamin C only in the same study2. In clinical trials with long follow-up periods analyzed in other reviews, vitamin C supplement use had no significant effect on the risk of myocardial infarction and stroke in subjects without diabetes17. The inconsistency of these findings may be partially explained by the presence of diabetes and the recommended daily intake of the vitamin. Vitamin C can act as a pro-oxidant interacting with free iron18 and among patients with DM an iron metabolism disorder seems to occur, with an increase in free iron stores19. Alternatively, vitamin C could have promoted protein glycation20 and stimulated lipid peroxidation21, with a possibly deleterious effect on the cardiovascular system as higher doses were administered. The daily vitamin C supplementation amount used was higher than the recommended daily intake for adults (90 mg/day for men and 75 mg/day for women), but lower than the maximum tolerable level (2000 mg/day)22.
Reduced serum levels of α-tocopherol were inversely associated with the incidence of coronary artery disease15, according to prospective observational studies in individuals without DM and/or without previous cardiovascular disease23,24. The α-tocopherol form of vitamin E is the most biologically active and could be considered a good biomarker of the consumption of this vitamin25. However, the beneficial effect observed in the study included in the current review occurred among users of antioxidant supplements, without specifying the supplement type and quantity15. Moreover, increased mortality from all causes3 in subjects without DM was demonstrated with 10-5000 IU/day of vitamin E supplementation in randomized clinical trials. A possible explanation of the adverse effects described is that vitamin E can inhibit platelet function26.
High serum zinc was shown to be protective against the development of cardiovascular disease16, a result that is in accordance with other studies in patients without DM27,28. Patients with type 2 DM presented lower values of serum zinc (9.23 µmol/L vs. 12.46 µmol/L, p < 0.001) compared with patients without DM, suggesting a lower antioxidant capacity in diabetes29. Possibly, the importance of maintaining high serum zinc values is due to their role in an endogenous antioxidant system30 and/or because zinc plays a clear role in the synthesis, storage and secretion of insulin31.
Chromium12 and selenium14, which were measured in the toenail, were not associated with cardiovascular outcomes in patients with DM in the studies included in this review. This result is different from what was observed in subjects without DM in a case-control study performed in eight European countries and Israel (EURAMIC study)32. In the EURAMIC study, chromium levels in nails was inversely associated with the occurrence of myocardial infarction (OR 0.59; 95%CI 0.37-0.95)32. Moreover, chromium33 and zinc31 are beneficial in regulating insulin action and energy metabolism. Better glycemic control could be reflected in lower cardiovascular outcomes34. In a recent systematic review with meta-analysis, chromium supplementation (1.28 to 1000 mcg/day) decreased the glycated hemoglobin values in 381 patients with DM by 0.6% (95%CI −0.9 to −0.2)35. However, cardiovascular outcomes were not evaluated in that study.
The study which evaluated selenium included in the current review was not in accordance with a recent meta-analysis of 25 observational studies36 that demonstrated a reduction of 24% (95%CI 7-38) in the risk of coronary artery disease with an increase of 50% in selenium levels (assessed by different methods). Selenium is another essential mineral involved in antioxidant defense, since it is part of glutathione peroxidase, a selenoprotein. In this context, low serum selenium has been linked to increased risk of cardiovascular disease in subjects without DM37. The effects of selenium supplementation (200 µg/day) in the prevention of cardiovascular events were not confirmed in a randomized clinical trial36 or in a prospective study having a follow-up of 7.6 years38, probably due to its narrow therapeutic range. Selenium deficiency in humans appears to be just one factor in a complex set of nutritional variables that may predispose or protect against cardiovascular disease37. One of the limitations common to studies with selenium and chromium included in this review involves the measurement method adopted. Although the levels of these minerals in the toenail may reflect the long-term intake of the mineral25, samples contamination could be a source of error12,14.
Our systematic review has several limitations: 1. the low quality of the original studies; 2. no study included meets all items previously established to evaluate methodological quality and potential confounding factors were considered in the analysis of data just from four studies12-14,16; 3. no sensibility analysis was carried out due to clinical heterogeneity of studies included; 4. the case-control studies did not allow us to establish a cause-consequence between micronutrients intake and cardiovascular outcomes. Also, the results for supplementation of vitamin C derived from a single cohort study and need to be considered with caution.In conclusion and according to available evidence, information about antioxidant micronutrient intake and cardiovascular risk in individuals with DM is too scarce to determine which micronutrient antioxidants might be related to cardiovascular outcomes in the DM population. Moreover, the antioxidant property of micronutrients appears to be only one factor in a complex set of nutritional variables that may predispose or protect against cardiovascular disease. Further studies should be performed to explore the relationship between antioxidant micronutrient intake and the development of cardiovascular disease in patients with DM, preferably randomized controlled trials. The description of the results of this review will aid researchers interested in investigating the topic to develop their hypotheses.
Conception and design of the research, Acquisition of data and Critical revision of the manuscript for intellectual content: Sarmento RA, Silva FM, Sbruzzi G, Schaan BD, Almeida JC; Analysis and interpretation of the data: Sarmento RA, Silva FM, Schaan BD, Almeida JC; Statistical analysis: Sarmento RA, Silva FM, Sbruzzi G, Schaan BD; Writing of the manuscript: Sarmento RA.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Sources of Funding
There were no external funding sources for this study.
This article is part of Roberta Aguiar Sarmento postgraduation final project at Instituto de Cardiologia - Fundação Universitária de Cardiologia do RS.
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Mailing Address: Manuscript received June 29, 2012; revised March 12, 2013; accepted March 25, 2013.
Jussara Carnevale de Almeida
Hospital de Clínicas de Porto Alegre
Rua Ramiro Barcelos, 2350 - Prédio 12, 4º andar
Postal Code 90035-003. Porto Alegre, RS - Brazil
Manuscript received June 29, 2012; revised March 12, 2013; accepted March 25, 2013.